Derivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones, process of preparation thereof and therapeutic application

ABSTRACT

Compounds of the formula ##STR1## in which R is H, .[.Cl, F, CH 3  or CF 3  .]. .Iadd.m-F, p-F, o-F, p-Cl, p-CH 3 , m-CH 3  or m-CF 3  .Iaddend.. The compounds are prepared by cyclizing with ethyl carbonate, a compound of the formula ##STR2## The compounds have anti-depressive, myorelaxing, tranquilizing, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities.

The present invention concerns novel derivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones, their process of preparation and their therapeutic application.

The compounds according to the present invention correspond to the general formula: ##STR3## in which R represents .[.a hydrogen atom, a halogen atom, an alkyl radical having 1 to 4 carbon atoms or a trifluoromethyl radical..]. .Iadd.m-F, p-F, o-F, p-Cl, p-CH₃, m-CH₃ or m-CF₃. .Iaddend.

The process for the preparation of the compounds according to the present invention comprises cyclising, by the action of ethyl carbonate, a 1-phenylamino-2,3-propanediol of the general formula: ##STR4## in which R has the same significance as in Formula I.

The following preparation is given, by way of non-limitative example, to illustrate the present invention.

EXAMPLE 5-hydroxymethyl-3-(m-trifluoromethyl phenyl)-2-oxazolidinone. (Code No. 68121)

59 G. OF 1-(M-TRIFLUOROMETHYL PHENYLAMINO)-2,3-PROPANEDIOL AND 118 G. OF ETHYL CARBONATE ARE INTRODUCED INTO A DISTILLATION APPARATUS. The mixture is progressively heated to about 110° C. when dissolution is obtained. Then, 12 ml. of a 5% solution of sodium methylate in methanol is added thereto. The distillation of the ethanol formed during the course of the reaction is then observed. Upon completion thereof any excess ethyl carbonate is removed under reduced pressure and the residue obtained is crystallized in isopropyl ether.

Melting point=80° C.

Yield=80%

Empirical formula=C₁₁ H₁₀ F₃ NO₃

Elementary analysis.--Calculated percent: C, 50.58; H, 3.86; N, 5.36. Found percent: C, 50,74; H, 3.76; N, 5.56.

The compounds listed in the following table have been prepared according to the process of the above example:

                                      TABLE I                                      __________________________________________________________________________      ##STR5##                                                                                                   Elementary analysis, percent                               Empirical                                                                              Mol M.P.                                                                               Yield,                                                                             Calculated                                                                              Found                                    Code No.                                                                            R   formula wt. ° C.                                                                        percent                                                                            C  H  N  C  H  N                                  __________________________________________________________________________     67360                                                                               H   C.sub.10 H.sub.11 NO.sub.3                                                             192.20                                                                             129 75  62.16                                                                             5.74                                                                              7.25                                                                              62.20                                                                             5.87                                                                              7.40                               68292                                                                               m-F C.sub.10 H.sub.10 FNO.sub.3                                                            211.19                                                                              96 87  56.87                                                                             4.77                                                                              6.63                                                                              56.88                                                                             4.92                                                                              6.79                               69155                                                                               p-F C.sub.10 H.sub.10 FNO.sub.3                                                            211.19                                                                             116 68  56.87                                                                             4.77                                                                              6.63                                                                              56.97                                                                             4.77                                                                              6.83                               69275                                                                               o-F C.sub.10 H.sub.10 FNO.sub.3                                                            211.19                                                                              94 60  56.87                                                                             4.77                                                                              6.63                                                                              56.75                                                                             4.73                                                                              6.67                               6922 p-Cl                                                                               C.sub.10 H.sub.10 ClNO.sub.3                                                           227.64                                                                             104 55  52.75                                                                             4.43                                                                              6.15                                                                              53.01                                                                             4.53                                                                              6.05                               69204                                                                               p-CH.sub.3                                                                         C.sub.11 H.sub.13 NO.sub.3                                                             207.22                                                                             145 66  63.75                                                                             6.32                                                                              6.76                                                                              63.93                                                                             6.10                                                                              6.88                               69276                                                                               m-CH.sub. 3                                                                        C.sub.11 H.sub.13 NO.sub.3                                                             207.22                                                                              76 70  63.75                                                                             6.32                                                                              6.76                                                                              63.70                                                                             6.43                                                                              6.78                               .[. 9217                                                                            o-CH.sub.3                                                                         C.sub.11 H.sub.13 NO.sub.3                                                             207.22                                                                              64 69  63.75                                                                             6.32                                                                              6.76                                                                              63.71                                                                             6.37                                                                              6.88.].                            __________________________________________________________________________

The compounds of Formula I experimentally exert anti-depressive. myorelaxing, tranquillising, sedative, analgesic, anti-convulsive, anti-pyretic, anti-inflammatory and uricosuric activities. Moreover, their toxic effects on animals in the laboratory are little marked.

(1) Anti-depressive properties.--The compounds of Formula I are capable of opposing hypothermia and the ptosis provoked by reserpine in the rat and the mouse, as well as the ulcers provoked by reserpine in the rat. Moreover, they oppose the catalepsy provoked by prochlorperazine in the rat.

By way of example, several results obtained are listed in the following table:

                                      TABLE II                                     __________________________________________________________________________                   Ptosis                                                           Hypothermia   Rat     Mouse   Ulcers                                                     Effect, Effect, Effect, Effect,                                      Code No.                                                                             Dose.sup.1                                                                         ° C.                                                                        Dose.sup.1                                                                         percent                                                                            Dose.sup.1                                                                         percent                                                                            Dose.sup.1                                                                         percent                                      __________________________________________________________________________     67360 200 -3.3                                                                               200 70  200 55  --  --                                           68121 100 -3.3                                                                               --  --  100 45  100 77                                           68292 100 -2.6                                                                               100 75  100 50  100 85                                           6922  --  --  100 45  100 55  --  --                                           69201 100 -2.9                                                                               --  --  --  --  --  --                                           69276 --  --  --  --  --  --  100 50                                           __________________________________________________________________________      .sup.1 Expressed in mg./kg./p.o.                                         

(II) Myorelaxing properties.--The compounds of Formula I provoke in the mouse the loss of the righting reflex and inhibit the traction reflexes and the maintenance on a rotating rod.

By way of example, the results obtained with two compounds of Formula I are listed in the following table:

                  TABLE III                                                        ______________________________________                                                                    Rotating rod                                        Code No. Traction test, ED.sub.50                                                                         test, ED.sub.50                                     ______________________________________                                         67360    300 mg./kg./p.o.  160 mg./kg./p.o.                                    68121                      110 mg./kg./p.o.                                    ______________________________________                                    

(III) Tranquillising and sedative action.--These effects are shown by a diminution of exploration curiosity in the enclose of an actimetric cage and of escape in an open field. The compound of Formula I reduce the aggressiveness provoked in the passage of an electric current and lower the body temperature of animals. The narcotic effects of penthiobarbital are equally reinforced.

The results obtained with two compounds of Formula I are listed in the following table:

                  TABLE IV                                                         ______________________________________                                                                     Potentialisation                                   Actimetric cage Evasion test                                                                               penthiobarbital                                                    Effect,       Effect,     Effect,                              Code No.                                                                               Dose.sup.1                                                                             percent Dose.sup.1                                                                           percent                                                                              Dose.sup.1                                                                           percent                              ______________________________________                                         67360    90     50      200   70    200   80                                   68121   100     70      --    --     80   50                                   ______________________________________                                          .sup.1 Expressed in mg./kg./p.o.                                         

(IV) Analgesic activity.--This activity is particularly pronounced against the painful stretching provoked in the mouse by the intraperitoneal administration of phenyl benzoquinone or acetic acid.

The results obtained with two compounds of Formula I are shown in the following table:

                  TABLE V                                                          ______________________________________                                                    Protection against                                                             phenylbenzoquinone                                                               Dose in       Effect,                                             Code No.     mg./kg./p.o.  percent                                             ______________________________________                                         67360        90            50                                                  68121        45            50                                                  ______________________________________                                    

(V) Anti-convulsive properties.--The compounds of Formula I exert in the mouse an antagonism against the lethal effects of cardiazol, strychnine and nicotine. They equally show activity against the tonic hyperextension of an excessive electric shock.

By way of example, the results obtained with several compounds of Formula I are listed in the following table:

                  TABLE VI                                                         ______________________________________                                                Antagonism against                                                             Cardizol  Strychnine  Nicotine                                                           Effect,       Effect,     Effect,                             Code No. Dose.sup.1                                                                             percent Dose.sup.1                                                                           percent                                                                              Dose.sup.1                                                                           percent                             ______________________________________                                         67360    --      --      140   50    --    --                                  68121    120     50      100   50    100   80                                  68292    --      --      100   70    100   60                                  6922     --      --      100   100   --    --                                  69155    --      --      100   65    --    --                                  ______________________________________                                          .sup.1 Expressed in mg./kg./p.o.                                         

(VI) Anti-pyretic action.--This action is manifested by a diminution of the experimental fever provoked by the administration of barm in the cat.

(VII) Anti-inflammatory effect.--The under-plantar oedema provoked in the rat by the administration of carraghenine is diminished by the compounds of the present invention.

(VIII) Uricosuric action.--After repeated oral administration in the rat, the compounds of Formula I provoke an augmentation of the urinary eliminations of uric acid.

In consequence of the results shown above, and the values appearing in the following table, the difference between the pharmacologically-active dose and the lethal dose is sufficiently great to enable the compounds of Formula I to be utilised in therapeutics.

                  TABLE VII                                                        ______________________________________                                         Code No.      LD50 P.O. (mouse,) mg./kg.                                       ______________________________________                                         67360         >1600                                                            68121         1400                                                             68292         1500                                                             6922          1050                                                             69155         1200                                                             69204         >4000                                                            69276         1850                                                             ______________________________________                                    

The compounds of Formula I are indicated in the case of depression and neurosis by depressive and anxious components. They equally possess a favourable effect against contractural and inflammatory pains, with or without hyperthermia.

They may be administered in the form of tablets and gelules containing 50 to 250 mg. of active ingredient.

Hence, according to the present invention there is also provided a therapeutic composition comprising a compound of Formula I together with a therapeutically-acceptable carrier. 

What we claim is: .[.1. A compound of the formula .Iadd. ##STR6##.Iaddend. in which R is selected from the group consisting of hydrogen, chlorine, fluorine, methyl and trifluoromethyl..]. .[.2. A compound as claimed in claim 1, in which R is chlorine or fluorine..]..Iadd.
 3. A compound of the formula .Iadd. ##STR7## .Iaddend. .Iadd.
 4. A compound of the formula .Iadd. ##STR8## .Iaddend. .Iadd.
 5. A compound of the formula .Iadd. ##STR9##.Iaddend. in which R is selected from the group consisting of p-methyl and m-methyl. .Iadd.
 6. A compound of the formula .Iadd. ##STR10## .Iaddend. .Iadd.
 7. A compound of the formula .Iadd. ##STR11##.Iaddend. 